Focus Group
Participants preferred unanimously tablets or capsules for adults and seniors, in a monthly frequency for adults and daily or weekly for seniors, especially those with multicompartment adherence aids (strong consensus). For infants, i.e. those who cannot be administered solid dosage forms, a weekly administration was unanimously preferred by the participants, with oily drops (strong consensus).
Reimbursement by health insurance was considered of moderate importance (mean+0.4, range –from -2 to +2). Physicians wanted to know if their patients were taking vitamin D (mean+1.5, range –from 0 to +2), even if they were not the prescribers, particularly in elderly people, for instance in cases of renal insufficiency or hypercalcaemia. This attitude was understandable for the other participants of the focus group.
Intervention Study
A total of 106 patients were enrolled between October 2017 and April 2018, i.e. winter months in Basel. Nine patients dropped out due to protocol violations, including failure to initiate treatment or missing the 3-month control visit (three patients each), and study termination due to nausea, hospitalization, or death (one patient each). 97 complete datasets were available for evaluation (Table 1).
Adherence related to dosage frequency
Taking adherence was significantly higher during the first three months of treatment compared to the second three months, independently of the formulation (99.0% vs. 94.7%; p=0.001; data not shown). Taking and timing adherence were significantly higher with monthly administration compared to weekly administration, independently of the formulation (Table 2).
Adherence related to pharmaceutical formulation
Within a dosage frequency (weekly or monthly), the adherence did not differ significantly between the pharmaceutical formulation (Table 2). From the returned bottles with a graduated pipette, 28% contained too much or too little expected residual volume. All participants returning bottles with clearly too much residual solution achieved suboptimal serum values.
Serum values
Patient’s baseline vitamin D values were similar in both solid and liquid preparations groups (p=0.108). The vitamin D values of all participants increased significantly in both treatment periods (p<0.001) and with each pharmaceutical formulation (Table 1). After two treatment periods, the values of solid and liquid formulations were similar (p=0.067).
Values in the reference range >50 nmol/l were not reached by 29% of participants after 3 months and by 9% after 6 months of treatment, respectively. Values in the optimal range of >75 nmol/l were reached by 18% of participants after 3, and 37% of them after 6 months of treatment, respectively. No values above the reference range were observed. The highest value measured in the study was 144 nmol/l.
Values in the optimal range of >75 nmol/l were reached by 32% of the participants with the solid dosage after the first treatment period, by 50% after the second treatment period. In the participants who were treated with drops, the proportion was 7% and 26% respectively.
Other biomarkers
With treatment, serum parathyroid hormone levels [pmol/l] decreased significantly from 7.75 at baseline to 7.30 after the first treatment period and 7.19 after the second treatment period (p=0.036). Similarly and as expected, mean serum phosphorus concentrations [mmol/l] increased under treatment from 1.51 (baseline) to 1.53 and 1.92 (p<0.001), serum alkaline phosphatase [IU/l] decreased from 83 (baseline) to 81 and 76 (p=0.001). Serum levels of all other biomarkers tested remained unchanged, e.g. mean serum calcium levels [mmol/l] were 2.41 (baseline), 2.40 (first treatment period) and 2.43 (second treatment period).
Adverse events
Adverse reactions were not serious nor could they be associated with hypercalcaemia (Table 3).
Preferences
From the 97 participants who finished the study, all gave their preferences for each formulation taken during three months (tablet vs. capsule or alcoholic vs oily drops), Regarding management (question 1) coping was more often bad and very bad with weekly drops compared with weekly tablets (Chi2=5.85; p=0.015). Regarding how pleasant the intake was (question 2), more participants indicated unpleasantness with liquid drops, independently of the frequencies (Chi2=18.4; p<0.01). Regarding frequencies (question 3), fewer individuals estimated that monthly intake was too frequent, independently of the formulation (Chi2=17.66; p<0.01).
A total of 29 patients (30%) had no preference for any galenic formulation (question 5). Of the 68 remaining participants, 71% (n=48) opted for a solid form, and 29% (n=20) for a liquid form (p<0.001). Half of the participants with prior experience of liquid formulations changed the sides. Only one patient who had taken capsules and tablets preferred the liquid forms.
When identical efficacy was assumed for different dosage frequencies (question 6), monthly intake was favored by 36.6% of the participants, weekly intake by 19.4%, annual intake by 11.8% and daily intake by 8.6%. Frequency did not matter for 23.7% of participants.
From the participants who had taken solid dosage forms, the type of formulation would not matter for 54%; 34% preferred capsules, and 12% tablets (question 7). Of those who had taken liquid dosage forms, the type of formulation did not matter for 24%; 72% preferred drops (oily or alcoholic formulation). The dosing pipette for the oily solution was considered a drawback for 53% of participants, and an advantage for 17% of them.